Insulin dependent diabetes (IDD) affects an estimated 1 in 300 persons in the U.S. Despite advances in management, most patients still develop life threatening macro and microvascular complications. No imminent therapeutic breakthroughs appear close to altering this situation anytime soon. An approach that attempts to delay the onset of IDD has therefore become increasingly attractive. IDD probably results from a chronic autoimmune ablation of pancreatic beta cells occurring over a time frame of years in most patients. Early reports of trails of non specific immunosuppressive therapy if given soon after diagnosis have suggested that the disease can be arrested however for most patients, this is too late, and the side effects too significant to contemplate indefinite continuance in those who do respond. Intervention must be earlier and more specific. This program project with 7 individual studies and 4 cores involving basic science and clinical investigators will examine the genetic susceptibility and pathogenic events in IDD in both man and non obese diabetic (NOD) mouse. One project will pursue the molecular genetics of HLA-D genes in human IDD, another the genetics of the class II MHC, T cell antigens, T cell receptors, and exon polymorphisms 5" to the insulin gene in NOD mice. New early disease markers will be sought by developing human and mouse insulinomas to identify beta cell surface reactive autoantibodies. Ways of identifying chronic lymphocyte activation to detect latent human IDD, will be explored using flow cytometry analyses and techniques of cellular immunology. Psychological stress as an inducer of human IDD will be evaluated. Extra pancreatic sites of insulin production will be examined in rodents, and the effects of diabetes on these processes will be studied in NOD mice. Redox perturbations and superoxide radical generation as a possible common ultimate pathway for beta cell necrosis will be studied in NOD mice and therapeutic manipulations to affect diabetic outcomes attempted.